rs4821478

Variant names:

• chr22-36294067-G-A
• rs4821478
• NM_002473.6:c.3837+25C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002473.6(MYH9):​c.3837+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,604,594 control chromosomes in the GnomAD database, including 342,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29113 hom., cov: 33)
  • Exomes 𝑓: 0.65 (313488 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.16
• Publications: 10 publications found

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

MYH9 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• May-Hegglin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-36294067-G-A is Benign according to our data. Variant chr22-36294067-G-A is described in ClinVar as Benign. ClinVar VariationId is 258745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.3837+25C>T		intron_variant	Intron 28 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.3837+25C>T		intron_variant	Intron 28 of 40	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.3900+25C>T		intron_variant	Intron 29 of 41			ENSP00000510688.1
MYH9	ENST00000691109.1	n.4132+25C>T		intron_variant	Intron 22 of 34

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92465 AN: 152026 Hom.: 29098 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.588 AC: 142978 AN: 243054 AF XY: 0.583

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.621

GnomAD4 exome AF: 0.648 AC: 940955 AN: 1452450 Hom.: 313488 Cov.: 43 AF XY: 0.641 AC XY: 463291 AN XY: 723056

African (AFR) AF: 0.524 AC: 17552 AN: 33470

American (AMR) AF: 0.648 AC: 28953 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 13540 AN: 26118

East Asian (EAS) AF: 0.221 AC: 8772 AN: 39684

South Asian (SAS) AF: 0.410 AC: 35387 AN: 86232

European-Finnish (FIN) AF: 0.663 AC: 29613 AN: 44652

Middle Eastern (MID) AF: 0.529 AC: 3024 AN: 5712

European-Non Finnish (NFE) AF: 0.690 AC: 767313 AN: 1111548

Other (OTH) AF: 0.610 AC: 36801 AN: 60320

GnomAD4 genome AF: 0.608 AC: 92519 AN: 152144 Hom.: 29113 Cov.: 33 AF XY: 0.601 AC XY: 44713 AN XY: 74376

African (AFR) AF: 0.530 AC: 22003 AN: 41490

American (AMR) AF: 0.645 AC: 9871 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1806 AN: 3470

East Asian (EAS) AF: 0.225 AC: 1161 AN: 5162

South Asian (SAS) AF: 0.382 AC: 1844 AN: 4826

European-Finnish (FIN) AF: 0.655 AC: 6940 AN: 10598

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.688 AC: 46762 AN: 67978

Other (OTH) AF: 0.598 AC: 1264 AN: 2112

Alfa AF: 0.645 Hom.: 8062

Bravo AF: 0.607

Asia WGS AF: 0.273 AC: 950 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 87% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 81. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.68
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4821478; hg19: chr22-36690113; COSMIC: COSV53395767; COSMIC: COSV53395767;